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PubMedDate not supplied

Effects of the aromatase inhibitor testolactone on human benign prostatic hyperplasia.

UNLABELLED: The aromatase inhibitor testolactone was used for endocrine treatment of benign prostatic hyperplasia (BPH). Thirteen patients (mean age 79 years) with complete urinary retention (BPH stage IV) without improvement after 4 weeks of bladder drainage by suprapubic catheter were treated with testolactone 100 mg, b.i.d., for 6 months. Nine men (mean age 80 years) with identical conditions who did not receive hormonal therapy served as controls. Results, treatment group: In 7 patients spontaneous micturation reoccurred after an average treatment period of 8 weeks (group A); 6 patients continued to need the catheter (group B). Prostatic volume decreased in all patients, and an average volume reduction of 26% was found in group A, whereas in group B the decrease averaged 15%. Finally, the testosterone/estradiol ratio significantly increased in all patients during treatment. CONTROL GROUP: Prostatic volume did not change nor did spontaneous micturation occur during the whole observation period.

Aged↗
PubMed1983

The effect of delta 1-testolactone on serum testosterone and estradiol in the adult male rat.

delta 1-Testolactone, an androgen derivative without intrinsic hormonal action, is known to block the aromatization of androgens to estrogens. This study was designed to assess its effect upon serum testosterone (T) and estradiol (E2) in the adult male rat. By itself, testolactone (TL) did not affect T/E2 levels in the dosages utilized. Daily injections of human chorionic gonadotropin (hCG) for 15 days caused a tenfold rise in serum T, although there was no increase in serum E2. When given along with hCG, TL did not alter the Leydig cell response. However, pretreatment of animals with TL increased the testicular response to hCG over that of saline-treated animals. Studies were also carried out to delineate the sources of estrogen in the adult male rat. These experiments demonstrate that (1) the majority of E2 is not testicular in origin but is derived from the adrenal; (2) the conversion of androgen precursors to E2 in the rat is not affected by TL; and (3) in spite of no demonstrable inhibition of E2 production, TL causes an increased Leydig cell responsiveness to hCG.

Animals↗
PubMed2003

Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone.

Studies from this laboratory have shown that obese men have elevated serum estrogen levels and diminished levels of follicle-stimulating hormone (FSH) and free and total testosterone, all in proportion to their degree of obesity. The decreases in testosterone and FSH constitute a state of hypogonadotropic hypogonadism (HHG), and we have hypothesized that it results from feedback suppression of the pituitary by the elevated estrogen levels. We tested this hypothesis by lowering the serum estrogens of 6 health obese men (body mass index [BMI], 38 to 73) by administering the aromatase inhibitor testolactone (1 g daily for 6 weeks). Twenty-four-hour mean serum testosterone rose in every subject, from a mean of 290 +/- 165 ng/dL to a mean of 403 +/- 170 (P <.0003); 24-hour mean serum estradiol decreased in every subject, from a mean of 40 +/- 10.8 pg/mL to a mean of 29 +/- 6.7 (P <.004); and 24-hour mean serum luteinizing hormone (LH) increased in every subject, from a mean of 14.3 +/- 4.1 mIU/mL to a mean of 19.3 +/- 5.1 (P <.004). The rise in mean LH was due to an increase in the amplitude of the individual secretory pulses, especially at night. Twenty-four-hour mean serum estrone decreased nonsignificantly, from 48 +/- 14 pg/mL to 39 +/- 6.4, and 24-hour mean serum FSH increased nonsignificantly, from 13.5 +/- 5.3 mIU/mL to 15.0 +/- 5.4. The results are in accordance with the hypothesis, in that inhibition of estrogen biosynthesis (through administration of the aromatase inhibitor testolactone) results in alleviation of the HHG of our obese male subjects.

Adult↗
PubMedDate not supplied

Effect of chronic aromatase inhibition by delta 1-testolactone on pituitary-gonadal function in oligozoospermic men.

Aromatase inhibition by delta 1-testolactone (Teslac, 500 mg twice daily) for 6 months in 9 patients with idiopathic oligozoospermia lowered the levels of serum estradiol (E2) and thereby sex hormone binding globulin (SHBG) (rS = +0.40, p less than 0.025) to values -35 and -25%, respectively, below the pretreatment values (P less than 0.001 and less than 0.005). The E2 decrease was accompanied by a temporary increase (+50%) in the levels of follicle stimulating hormone (FSH), not of luteinizing hormone (LH), and of 17 alpha-hydroxyprogesterone (17 alpha-OHP), but less of testosterone (T) (+30%), which led to a transient rise in the 17 alpha-OHP/T ratio. The T/E2 ratio and "free T" index (T/SHBG) almost doubled until the end of the treatment period. During delta 1-testolactone treatment the mean sperm density gradually rose from 8.1 +/- 1.3 (SEM) before to 21.3 +/- 6.7 X 10(6)/ml after 6 months (P less than 0.01), whereas the total sperm count almost threefold increased (P less than 0.05). Sperm concentrations exceeding 20 X 10(6)/ml were achieved in 4 of the 9 patients. Two of these patients' wives became pregnant. Although the data point to a pivotal role of estrogens in the pathogenesis of the spermatogenic lesion in some patients with idiopathic oligozoospermia, the lack of a beneficial effect of estrogen lowering in others points to a multicausal nature of the disease entity.

Adult↗
PubMed1993

Treatment of familial male precocious puberty with spironolactone, testolactone, and deslorelin.

Combined antiandrogen (spironolactone) and aromatase inhibitor (testolactone) are effective for the short term treatment of familial male precocious puberty. During this therapy, plasma testosterone levels remain in the adult range, since spironolactone blocks the testosterone receptor without significantly affecting plasma testosterone levels. After our initial 18-month pilot study, we continued to treat eight boys with the combined therapy for 2.0-4.2 yr. During this time all boys exhibited a pubertal rise in gonadotropin secretion and a diminishing response to treatment, which was manifested by the recurrence of clinical features of puberty and an increase in the bone maturation rate (P < 0.05). Addition of the LHRH agonist deslorelin (4 micrograms/kg.day, sc) to the combined therapy decreased peak LH, plasma testosterone, bone maturation rate, and growth velocity (P < 0.05) over the next year. We conclude that the rise in gonadotropin levels during central activation of hypothalamic LHRH secretion in boys with familial male precocious puberty causes a partial escape from the combined effect of spironolactone and testolactone. The addition of deslorelin to the combined therapy appears to restore the control of puberty in this setting.

Age Determination by Skeleton↗
PubMed1986

Treatment of pubertal gynaecomastia with testolactone.

22 Boys with pubertal gynaecomastia (age 15.9 +/- 1.9 years) were treated with testolactone (450 mg daily by mouth) for 2 to 6 months without side-effects. The mean breast gland diameter regressed from 4.4 to 3.3, 3.2 cm, and 1.7 cm at 2, 4, and 6 months, while pubic hair and testicular volume progressed normally. Plasma androstenedione increased from 5.4 to 73.1 nmol/l. Testosterone, DHEA, and oestrone increased less, and oestradiol remained unchanged. Androgen/oestrogen ratios increased (most marked change: androstenedione/oestrone from 15 to 140). LH (basal and maximum after LHRH) did not change, but FSH increased somewhat (basal 133 to 173, maximum 225 to 269 micrograms/l). Prolactin remained unchanged. It is concluded that testolactone, an inhibitor of steroid aromatization, is an effective and safe medical treatment for pubertal gynaecomastia.

Adolescent↗
PubMed1991

[Therapeutic efficacy of testolactone (aromatase inhibitor) to oligozoospermia with high estradiol/testosterone ratio].

To our knowledge, the action of estradiol which is produced from testosterone by aromatase on human spermatogenesis has not been fully clarified. In oligozoospermia, with high values of E2/T ratio, it is considered that the role of estradiol is suppressive to spermatogenesis. In this study, alteration of spermatogenesis was evaluated when serum estradiol levels were decreased by suppression of aromatase activity. Nine male infertile patients were treated with testolactone (Teslac: 1.0 g/day, for 3 months), one of the aromatase inhibitors. Four of them had an increase in sperm count (more than 10 x 10(6)/ml relative to base line). In endocrinological findings, serum estradiol levels and E2/free T ratio were significantly decreased after treatment. Serum free testosterone levels were significantly increased in all cases, presumably from decreased sex hormone binding globulin (SHBG) levels. These findings suggested the effectiveness of the administrated aromatase inhibitor. In particular four patients whose sperm counts were improved after testolactone treatment had high values of basal serum estradiol levels and E2/free T ratio before treatment, and these values were normalized after treatment. In conclusion we suggest that an aromatase inhibitor may be effective to male infertile patients with high serum estradiol levels.

Adult↗
PubMed1985

Human male sexual functions do not require aromatization of testosterone: a study using tamoxifen, testolactone, and dihydrotestosterone.

This study was designed to examine whether testosterone needs to be converted to estradiol in order to exert fully its effects on sexuality in the human male. Administration of the estrogen receptor antagonist tamoxifen and the aromatase inhibitor testolactone were without effect on parameters of sexual functions. Replacement of testosterone substitution therapy of agonadal men by dihydrotestosterone was likewise not associated with any change of sexual functioning. Administration of dihydrotestosterone to eugonadal men led to a transient increase of nocturnal sexual dreams and erections and irritability, waning after 3-4 weeks of dihydrotestosterone administration. It is concluded that aromatization of testosterone is not required and that dihydrotestosterone maintains sexual functions in the adult male with an established sex life.

Adult↗
PubMed1985

Effect of aromatase inhibition by delta 1-testolactone on basal and luteinizing hormone-releasing hormone-stimulated pituitary and gonadal hormonal function in oligospermic men.

Aromatase inhibition by delta 1-testolactone (TL), 500 mg twice daily for 4 weeks, in nine patients with idiopathic oligospermia lowered circulating estradiol (E2) levels by about 30%, enhanced the secretion of follicle-stimulating hormone (+ 30%), 17-hydroxyprogesterone (17-OHP) (+ 40%), and testosterone (T) (+ 30%), but did not affect serum luteinizing hormone levels. Despite E2 lowering, there was an accumulation of 17-OHP over T, suggesting 17, 20-lyase inhibition. Unexpectedly, administration of TL almost completely deleted the T response to continuous luteinizing hormone-releasing hormone infusion present before TL therapy, despite similar gonadotropin release. Because the 17-OHP response to the luteinizing hormone-releasing hormone infusion was even higher during therapy, the 17,20-lyase lesion seemed aggravated despite substantial reduction of E2 levels. Although the present data suggest that estrogens play a less dominant role in the origin of the late steroidogenetic lesion than previously assumed, the suggestion also arises that TL per se, in addition to its antiestrogenic action, exerts an inhibiting effect on the 17,20-lyase locus, which may obscure the beneficial effect of reducing E2.

Adult↗
PubMed1985

Short-term effects of testolactone on human testicular steroid production and on the response to human chorionic gonadotropin.

Testicular responsiveness to a single dose of human chorionic gonadotropin was studied in five normal men before and during short-term treatment with an aromatization inhibitor, testolactone (TL). TL alone resulted in significant increases in the serum concentrations of progesterone, 17-hydroxyprogesterone, 17-hydroxypregnenolone, dehydroepiandrosterone, androstenedione, and the sulfate conjugates of pregnenolone, 17-hydroxypregnenolone and testosterone (T). Concentrations of 5-androstene-3 beta, 17 beta-diol and T remained unchanged, and those of estradiol (E2) decreased. TL had no major influence on serum luteinizing hormone, follicle-stimulating hormone, prolactin, or sex-hormone-binding globulin concentrations. During TL administration, human chorionic gonadotropin stimulation led to a significantly decreased E2 response, but the T response was unchanged. Alleviation of an inhibitory influence of E2 on the steroidogenic enzymes, especially 17,20-desmolase, was probably the reason behind the increased synthesis of several T precursors. In addition, TL appeared to have an inhibitory influence on the 17 beta-reduction of T precursors. TL resulted in increased serum concentrations of some steroid sulfates, but the mechanism of this effect remains unclear.

Adult↗
PubMedDate not supplied

Estrogens in the feedback regulation of gonadotropin secretion in men: effects of administration of estrogen to agonadal subjects and the antiestrogen tamoxifen and the aromatase inhibitor delta'-testolactone to eugonadal subjects.

To elucidate the specific role of estrogens in the feedback regulation of gonadotropin secretion in men, basal and LRH-stimulated gonadotropin levels were studied in: Six agonadal subjects Six agonadal subjects continuously treated with 50 micrograms ethinylestradiol Six eugonadal subjects, treated with the aromatase inhibitor delta'-testolactone, which induced a reduction of estrogen levels, independently of testosterone. Further, to determine whether estrogens exert differential effects in time on LH and FSH secretion, the anti-estrogen tamoxifen was administered to: Six eugonadal subjects for two weeks and Six eugonadal subjects for six weeks. It was found that estrogens have a strong suppressive effect on both LH and FSH secretion. However, changes in estrogen levels and blocking of estrogen receptors are followed more rapidly by FSH than LH. Estrogens affect LRH-induced LH release more than basal LH levels; basal and LRH-stimulated FSH are approximately equally influenced. Basal and LRH-induced LH secretion are known to be more dependent upon previous LRH stimulation than FSH secretion. Since FSH followed changes of estrogens more rapidly than LH did, we postulate that the negative feedback action of estrogens on: LH secretion is predominantly exerted at the level of the hypothalamus, through inhibition of LRH secretion FSH secretion predominantly at the level of the pituitary through a direct action on the gonadotroph.

Adult↗
PubMed1988

Tamoxifen and testolactone in therapy of oligozoospermia: results of a randomized study.

40 patients with oligoasthenozoospermia in infertile marriages were subjected to randomized treatment with 30 mg tamoxifen/day (n = 20), or with 30 mg tamoxifen/day and 150 mg testolactone/day (n = 20), to prevent elevation of estradiol levels during monotherapy with tamoxifen. In both groups there was a significant increase in FSH, LH and testosterone. The elevation of estradiol serum levels was significant (p less than 0.0001) in the tamoxifen group, and not significant in the group with combination therapy. The increase in sperm density was significant in both groups (p less than 0.001; p less than 0.002, respectively), but no differences were seen between both groups. No improvement of the other ejaculate parameters was seen in either groups. The incidence of gravidity was the same under additional testolactone therapy (n = 3).

Drug Therapy, Combination↗
PubMed1982

The antiandrogenic effects of delta 1-testolactone (Teslac) in vivo in rats and in vitro in human cultured fibroblasts, rat mammary carcinoma cells, and rat prostate cytosol.

The antiandrogenic properties of delta 1-testolactone (17 alpha-oxa-D-homo-1,4-androstane-3,17-dione; Teslac) were investigated in vivo and in vitro. Teslac (75 mg/day for 7 days) inhibited the rise in ventral prostate weight induced by testosterone (T) (P less than 0.001), dihydrotestosterone (DHT) (P less than 0.05), and a combination of T plus 17 beta-estradiol (E2) (P less than 0.01) in immature castrate rats. Similar effects were seen on the seminal vesicles after T and T plus E2 (P less than 0.001). Teslac also decreased prostate and seminal vesicle weights in intact immature rats. The effects of Teslac were dose and time dependent. Teslac did not change the concentration of serum T or DHT. However, Teslac inhibited DHT binding to the androgen receptor (Ki = 2.5 +/- 0.8 X 10(-7) M) in cytosol of the rat prostate. Teslac also inhibited DHT binding to the androgen receptor in cultured human prepuce fibroblasts and cultured rat mammary tumor cells (Ki = 1.9 +/- 0.3 X 10(-5) M). The results indicate that Teslac, in addition to its antiaromatase activity, is an antiandrogen by virtue of its interaction with the androgen receptor.

Androgen Antagonists↗
PubMed1981

Effects of delta 1-testolactone on the pituitary-testicular axis in oligospermic men.

Ten men with idiopathic oligospermia were treated with delta 1-testolactone (Teslac), a potent inhibitor of conversion of androgens to estrogens. Teslac therapy caused a fall in serum estradiol and estrone levels of 34% (P less than 0.01) and 41% (P less than 0.01), respectively, and a rise in serum testosterone and androstenedione of 47% (P less than 0.02) and 70% (P less than 0.01), respectively. The testosterone-estradiol ratio increased by 126% (23.5 +/- 2.5 x 10(-1) to 45.2 +/- 5.0 x 10(-1); P less than 0.01) and the androstenedione:estrone ratio increased 231% (4.7 +/- 0.6 x 10(-1) to 12.9 +/- 2.0 x 10(-1); P less than 0.01). Basal and LRH-stimulated serum gonadotropin levels were unaffected by these changes. Sperm density rose from 10.8 +/- 2.5 to 19.8 +/- 4.7 x 10(6)/ml (P less than 0.01) and total sperm count from 26.8 +/- 6.5 to 60.6 +/- 14.3 x 10(6) (P less than 0.001). There was no significant change in motility or semen volume. Three of the wives became pregnant. There were no adverse effects of Teslac administration. These data suggest that Teslac may be an effective treatment for men with idiopathic oligospermia. Though the data do not clearly elucidate the mechanism of this effect, they are consistent with the possibility that Teslac's lowering of estrogen levels may have been responsible for the improvement in spermatogenesis. The findings also suggest that moderate increases in the circulating androgen-estrogen ratio do not affect gonadotropin output in men.

Adult↗
PubMed1985

The effects of the aromatase inhibitor delta 1-testolactone on gonadotropin release and steroid metabolism in polycystic ovarian disease.

This study was designed to examine the importance of aromatization in the gonadotropin secretory dynamics of polycystic ovarian disease (PCOD) by using the aromatase inhibitor delta 1 testolactone (TL) as a probe and to determine the effects of TL on steroid metabolism in vivo and in vitro. The pulsatile patterns of gonadotropin secretion and peripheral steroid levels were studied in eight women with PCOD before and during TL administration. There was a significant fall in peripheral estrone (E1) levels, a rise in peripheral androstenedione levels, and an increase in the androstenedione/E1 ratio during TL administration in these women. Isotopic determinations of androgen and estrogen production and metabolism before and during TL administration in two women confirmed a 90-95% decrease in the overall rate of aromatization. One patient also had an increase in the production and clearance rates of estradiol and E1 during TL administration, suggesting resistance to TL of the ovarian aromatase enzyme system. There were significant increases in both mean LH pulse amplitude [1.2 +/- 0.3 (SE) mIU/ml LER-907 before vs. 1.7 +/- 0.3 mIU/ml LER-907 during TL, P less than 0.05, paired t test] and frequency per 6 h (median: 3 before vs. 4 during TL, P less than 0.05, Wilcoxon signed rank test). Mean levels of LH and FSH did not, however, change significantly during TL administration. TL maximally inhibited neonatal rat hypothalamic aromatase in vitro at concentrations of 200 microM, a level theoretically obtainable during pharmacological therapy. These data suggest that: 1) in humans TL is a potent inhibitor of peripheral but not ovarian aromatase, and of hypothalamic aromatase in rats; 2) TL administration increases LH pulse amplitude and frequency in PCOD, either directly via hypothalamic aromatase inhibition, or indirectly by alterations in gonadal steroid metabolism; and 3) because of the multiple potential actions of TL, its usefulness as a probe in studies of gonadotropin secretion in PCOD is limited.

Adult↗
PubMed1998

Testosterone versus testosterone and testolactone in treating reproductive and sexual dysfunction in men with epilepsy and hypogonadism.

Antiepileptic drug-induced reductions in serum levels of biologically active testosterone and elevations in serum estradiol (E2) may contribute to sexual dysfunction among men with epilepsy. Treatment using a combination of testosterone and the aromatase inhibitor testolactone may have significantly better effects on sexual function and also seizure frequency than testosterone alone.

Adult↗
PubMed1980

Intraarterial 5-FU infusion with or without oral testolactone treatement in irresectable pancreatic cancer.

The results of a prospective study of 19 patients with pancreatic cancer treated with regional intraarterial 5-FU infusion with or without oral tesolactone are reported. No primary mortality was noted. No measurable tumor remission was seen. The median survival time from the state of infusion therapy was 6.5 months. Median time of hospitalization from the start of infusion therapy was 2 months, which corresponds approximately to 30% of remaining survival time. No significant improvement of quality of life was registered during the treatment period. The results indicate that intrrarterial regional 5-FU--neither with nor without testolactone--cannot be recommended for patients with irresectable pancreatic cancer.

Adult↗